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While bromocriptine is currently in use as a T2DM therapeutic, its mechanism(s) of action is not well characterized. Bromocriptine may act to reduce blood glucose through homeostatic mechanisms via ‘resetting’ dopaminergic tone and suppressing hepatic glucose production (5,6), hedonic mechanisms by altering basal and evoked dopaminergic response, or both. Moreover, based on marked differences in person-to-person drug efficacy, there is evidence for modulation of its effects by a genetic component. Our decision to focus on bromocriptine in the context of the present study is three fold:
1) Homeostatic regulation: Bromocriptine is thought to augment low hypothalamic dopamine and suppresses hepatic glucose production, lipolysis, and lipogenesis. In support, bromocriptine treatment results in decreased postprandial plasma glucose, improved insulin sensitivity and lipid profiles in humans with T2DM (7,8) and reduction in both body fat and hyperphagia in animals (6,9).
2) Hedonic regulation: Bromocriptine also may impact hedonic responsivity to food stimuli (e.g., ad lib food intake, impulse control), as it directly augments dopamine-D2 function. Obese vs lean humans have decreased dopamine-D2 binding (10–12) and show reduced striatal response to palatable food intake (13,14); prelim data) and bromocriptine has altered food reinforcement and chow intake in mice (15).
3) Genetic regulation: As a dopamine-D2 agonist, efficacy of bromocriptine is dependent on dopamine signaling capacity. Thus, genetic polymorphisms of the dopamine-D2 receptor (DRD2) gene may impact bromocriptine effectiveness through neural and/or hormonal mechanism. Notably, the DRD2 TaqIA A1 allele is associated with reduced dopamine-D2 receptor density and dopamine signaling, and is disproportionately prevalent in the T2DM population (16,17).
Despite the evident interaction among dopaminergic functioning, T2DM management, and food intake, the mechanisms of action and effect of bromocriptine on homeostatic and hedonic regulators of food intake remains largely unknown. The present investigation would be one of the first to experimentally manipulate dopaminergic functioning via acute bromocriptine administration and assess neural, behavioral and perceptual hedonic responses to food while simultaneously evaluating homeostatic satiation signaling in those at high risk for development of T2DM. This study will also provide vital knowledge about the effectiveness of the D2 agonist bromocriptine by determining the impact of the DRD2 TaqIA A1 genetic polymorphism on drug response, thereby informing the basis for personalized medicine in this population.